The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
Date of Graduation
Doctor of Philosophy (PhD)
Wei Cao, Ph.D.
Shao-Cong Sun, Ph.D.
Roza Nurieva, Ph.D.
Kenneth Tsai, M.D., Ph.D.
Chengming Zhu, Ph.D.
Kevin McBride, Ph.D.
Humoral autoimmunity is characterized by the breakdown of B cell immune tolerance to self-antigens and consequent production of pathogenic autoantibodies. Plasmacytoid dendritic cells (pDCs), a potent type I interferon (IFN-I) producer, have been linked to the pathogenesis of systemic lupus erythematosus (SLE), a prototypic systemic humoral autoimmune disease. However, the cellular events that stimulate the development of humoral autoimmunity as a result of pDC activation have not been characterized. Moreover, the B cell subset(s) responsible for the generation of autoantibodies remains to be clearly identified.
The immunization of DNA-containing amyloids into non-autoimmune mice triggers the activation of pDCs and induction of lupus-like disease, characterized by the production of autoantibodies. Using this lupus model that is dependent on pDC activation and IFN-I production, we delineated the B cell responses elicited during the break of tolerance and characterized the key cellular players that may influence those responses. We found that, when IgM autoantibodies were induced, germinal centers were inhibited whereas immature B cells were activated and expanded. Such interesting observation suggested that humoral autoimmunity may arise from B cells outside germinal centers. While pDCs were involved in the overt activation of immature B cells, type II interferon (IFN-II) promoted their expansion. In addition, both IFN-I and IFN-II were required for isotype-class switch of autoantibodies thereby the generation of pathogenic subtypes. We further determined that IFN-II was produced by natural killer (NK) cells, which contributed to the development of humoral autoimmunity. In contrast, NKT cells suppressed the autoimmune B cell response. Last, we demonstrated that serum amyloid P-component, a humoral factor that binds to amyloids, prevented the activation of pDCs and IFN-I production thus may exert a protective role against humoral autoimmunity.
Our results established a functional link between IFN-I and IFN-II, where IFN-I from pDCs and IFN-II from NK cells are essential in stimulating multiple types of adaptive immune cells to coordinate the differentiation and expansion of self-reactive B cells. Selective targeting of the key cellular and molecular players may lead to innovative therapies for SLE and other autoimmune diseases.
Humoral autoimmunity, plasmacytoid dendritic cells, interferon, B cells, autoantibodies, NK cells, SLE, lupus, serum amyloid P-component, amyloids
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